The B cell antigen receptor (BCR) serves dual, interrelated functions in B cell activation. The first is to initiate signal cascades that result in the transcription of a variety of genes associated with B cell activation. The second is to traffic bound antigen into the cell providing at least two important functions. The first is to deliver the antigen into intracellular compartments where the antigen is proteolytically cleaved and the resulting peptides are assembled into MHC class II-peptide complexes. The MHC class II-peptide complexes are expressed on the B cell surface for recognition by helper T cells that will as a consequence be activated to provide essential growth and differentiation factors to the B cell. The second is to deliver complexes of antigen and nucleic acids to intracellular compartments that contain toll like receptors (TLRs) the activating ligands for which are DNA and RNA oligonucleotides. The signaling and antigen transport functions of the BCR are interdependent in that the BCR signaling is necessary for the correct and rapid targeting of the antigen. In addition to the transport functions of the BCR, the internalization of the BCR may play an important role in regulating signaling by removing activated receptors from the cell surface. At present it is not known if the antigen targeting and BCR down regulation are one in the same or separable processes. The long term goal of this program is to define the cellular and molecular mechanism by which the BCR transports antigens to the appropriate intracellular compartments and is removed from the surface to regulate signaling. Concerning the mechanism of BCR transport to the MHC class II compartments we previously showed that the EBV latent membrane protein 2A (LMP2A) blocked BCR trafficking. Genetic analyses of the cytoplasmic domain of LMP2A showed that mutations in the Lyn-binding site allowed internalization and degradation of the BCR but not trafficking to the peptide class II assembly compartment. Recent studies have provided evidence that the LMP2A expressing cells do not activate phospholipase D (PLD) in response to BCR crosslinking suggesting that PLD plays a critical role in targeting the BCR to the class II compartments. We are currently exploring the effects of blocking PLD activity in BCR signaling and trafficking and have introduced the LMP2A gene into mouse B cells where reagents are available to more thoroughly analyze the LMP2A-induced block on antigen processing.